Professional Documents
Culture Documents
Guide To Good Prescribing
Guide To Good Prescribing
Guide To Good Prescribing
11
Distr: General
Original: English
WHO/DAP/94.11
Distr: General
Original: English
A
uthors
T. P. G. M. de Vries
1
R. H. Henning
2
H. V. Hogerzeil
2
D. A. Fresle
Acknowledgments
The support of the following persons in reviewing earlier drafts of this book is
gratefully acknowledged: S.R. Ahmad (Pakistan), A. Alwan (WHO), F.S. Antezana
(WHO), J.S. Bapna (India), W. Bender (Netherlands), L. Bero (USA), S. Berthoud
(France), K. Besseghir (Iran), C. Boelen (WHO), P. Brudon-Jakobowicz (WHO),
P. Bush (USA), M.R. Couper (WHO), M. Das (Malaysia), C.T. Dollery (United
Kingdom), M.N.G. Dukes (Netherlands), J.F. Dunne (WHO), H. Fraser (Barbados),
M. Gabir (Sudan), B.B. Gaitonde (India), W. Gardjito (Indonesia), M. HellingBorda (WHO), A. Herxheimer (United Kingdom), J. Idnpn-Heikkil (WHO), K.K.
Kafle (Nepal), Q.L. Kintanar (Philippines), M.M. Kochen (Germany), A.V.
Kondrachine (WHO), C. Kunin (USA), R. Laing (Zimbabwe), C.D.J. de Langen
(Netherlands), V. Lepakhin (USSR), A. Mabadeje (Nigeria), V.S. Mathur (Bahrain),
E. Nangawe (Tanzania), J. Orley (WHO), M. Orme (United Kingdom), A. Pio (WHO),
J. Quick (USA), A. Saleh (WHO), B. Santoso (Indonesia), E. Sanz (Spain),
F. Savage (WHO), A.J.J.A. Scherpbier (Netherlands), F. Siem Tjam (WHO),
F. Sjqvist (Sweden), A. Sitsen (Netherlands), A.J. Smith (Australia), J.L. Tulloch
(WHO), K. Weerasuriya (Sri Lanka), I. Zebrowska-Lupina (Poland), Z. Ben Zvi
(Israel).
The following persons gave invaluable assistance in field testing the draft, and their
support is gratefully acknowledged: J.S. Bapna (India), L. Bero (USA), K.K. Kafle
(Nepal), A. Mabadeje (Nigeria), B. Santoso (Indonesia), A.J. Smith (Australia).
Illustrations on p. 56, 72: B. Cornelius (with permission from Vademecum); p. 7:
P. ten Have; annexes and cartoon on p. 22: T.P.G.M. de Vries.
iii
Contents
T
able of contents
W
hy you need this book.....................................................................................................
Part 1: Overview ...................................................................................................................
Chapter 1:
Introduction to P-drugs...............................................................................
Chapter 3:
Chapter 4:
Chapter 5:
Chapter 7:
Chapter 8:
Chapter 9:
Annex 2:
Essential references...................................................................................
Annex 3:
Annex 4:
L
ist of patient examples
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
ii
At the start of clinical training most medical students find that they don't have a very
clear idea of how to prescribe a drug for their patients or what information they need
to provide. This is usually because their earlier pharmacology training has
concentrated more on theory than on practice. The material was probably 'drugcentred', and focused on indications and side effects of different drugs. But in
clinical practice the reverse approach has to be taken, from the diagnosis to the
drug. Moreover, patients vary in age, gender, size and sociocultural characteristics,
all of which may affect treatment choices. Patients also have their own perception of
appropriate treatment, and should be fully informed partners in therapy. All this is
not always taught in medical schools, and the number of hours spent on
therapeutics may be low compared to traditional pharmacology teaching.
Clinical training for undergraduate students often focuses on diagnostic rather than
therapeutic skills. Sometimes students are only expected to copy the prescribing
behaviour of their clinical teachers, or existing standard treatment guidelines,
without explanation as to why certain treatments are chosen. Books may not be
much help either. Pharmacology reference works and formularies are drug-centred,
and although clinical textbooks and treatment guidelines are disease-centred and
provide treatment recommendations, they rarely discuss why these therapies are
chosen. Different sources may give contradictory advice.
The result of this approach to pharmacology teaching is that although
pharmacological knowledge is acquired, practical prescribing skills remain weak. In
one study, medical graduates chose an inappropriate or doubtful drug in about half
of the cases, wrote one-third of prescriptions incorrectly, and in two-thirds of cases
failed to give the patient important information. Some students may think that they
will improve their prescribing skills after finishing medical school, but research
shows that despite gains in general experience, prescribing skills do not improve
much after graduation.
Bad prescribing habits lead to ineffective and unsafe treatment, exacerbation or
prolongation of illness, distress and harm to the patient, and higher costs. They
also make the prescriber vulnerable to influences which can cause irrational
prescribing, such as patient pressure, bad example of colleagues and highpowered salesmanship. Later on, new graduates will copy them, completing the
circle. Changing existing prescribing habits is very difficult. So good training is
needed before poor habits get a chance to develop.
This book is primarily intended for undergraduate medical students who are about
to enter the clinical phase of their studies. It provides step by step guidance to the
process of rational prescribing, together with many illustrative examples. It teaches
skills that are necessary throughout a clinical career. Postgraduate students and
practising doctors may also find it a source of new ideas and perhaps an incentive
for change.
Its contents are based on ten years of experience with pharmacotherapy courses
for medical students in the Medical Faculty of the University of Groningen
(Netherlands). The draft has been reviewed by a large body of international experts
in pharmacotherapy teaching and has been further tested in medical schools in
Australia, India, Indonesia, Nepal, Netherlands, Nigeria and the USA (see Box 1).
Box 1:
The impact of a short interactive training course in pharmacotherapy, using the Guide to Good
Prescribing, was measured in a controlled study with 219 undergraduate medical students in
Groningen, Kathmandu, Lagos, Newcastle (Australia), New Delhi, San Francisco and
Yogyakarta. The impact of the training course was measured by three tests, each containing
open and structured questions on the drug treatment of pain, using patient examples. Tests
were taken before the training, immediately after, and six months later.
After the course, students from the study group performed significantly better than controls in all
patient problems presented (p<0.05). This applied to all old and new patient problems in the
tests, and to all six steps of the problem solving routine. The students not only remembered how
to solve a previously discussed patient problem (retention effect), but they could also apply this
knowledge to other patient problems (transfer effect). At all seven universities both retention and
transfer effects were maintained for at least six months after the training session.
This manual focuses on the process of prescribing. It gives you the tools to think for
yourself and not blindly follow what other people think and do. It also enables you
to understand why certain national or departmental standard treatment guidelines
have been chosen, and teaches you how to make the best use of such guidelines.
The manual can be used for self-study, following the systematic approach outlined
below, or as part of a formal training course.
Part 1: The process of rational treatment
This overview takes you step by step from problem to solution. Rational treatment
requires a logical approach and common sense. After reading this chapter you will
know that prescribing a drug is part of a process that includes many other
components, such as specifying your therapeutic objective, and informing the
patient.
Part 2: Selecting your P-drugs
This section explains the principles of drug selection and how to use them in
practice. It teaches you how to choose the drugs that you are going to prescribe
regularly and with which you will become familiar, called P(ersonal)-drugs. In this
selection process you will have to consult your pharmacology textbook, national
formulary, and available national and international treatment guidelines. After you
have worked your way through this section you will know how to select a drug for a
particular disease or complaint.
Part 3: Treating your patients
This part of the book shows you how to treat a patient. Each step of the process is
described in separate chapters. Practical examples illustrate how to select,
2
prescribe and monitor the treatment, and how to communicate effectively with your
patients. When you have gone through this material you are ready to put into
practice what you have learned.
Part 4: Keeping up-to-date
To become a good doctor, and remain one, you also need to know how to acquire
and deal with new information about drugs. This section describes the advantages
and disadvantages of different sources of information.
Annexes
The annexes contain a brief refresher course on the basic principles of
pharmacology in daily practice, a list of essential references, a set of patient
information sheets and a checklist for giving injections.
A word of warning
Even if you do not always agree with the treatment choices in some of the
examples it is important to remember that prescribing should be part of a
logical deductive process, based on comprehensive and objective information.
It should not be a knee-jerk reflex, a recipe from a 'cook-book', or a response
to commercial pressure.
Drug names
In view of the importance that medical students be taught to use generic names,
the International Nonproprietary Names (INNs) of drugs are used throughout the
manual.
Comments
The WHO Action Programme on Essential Drugs would be very glad to receive
comments on the text and examples in this manual, as well as reports on its use.
Please write to: The Director, Action Programme on Essential Drugs, World Health
Organization, 1211 Geneva 27, Switzerland. Fax 41-22-7914167.
Part 1
Overview
P art 1:
Overview
Chapter 1
page
The process of rational treatment.........................................................................6
What is your first-choice treatment for dry cough?.......................................7
The process of rational prescribing..............................................................9
Conclusion and summary..........................................................................10
C hapter 1
Chapter 1
In fact, there are two important stages in choosing a treatment. You start by
considering your first-choice treatment, which is the result of a selection process
done earlier. The second stage is to verify that your first-choice treatment is
suitable for this particular patient. So, in order to continue, we should define our
first-choice treatment for dry cough.
Cartoon 1
In summary, treatment of dry cough may consist of advice to avoid irritation of the
lungs, and/or suppression of the cough by a drug.
Choose your P-treatment on the basis of efficacy, safety, suitability and cost
The next stage is to compare the various treatment alternatives. To do this in a
scientific and objective manner you need to consider four criteria: efficacy, safety,
suitability and cost.
Chapter 1
If the patient is willing and able to follow advice to avoid lung irritation from smoking
or other causes, this will be therapeutically effective, since the inflammation of the
mucous membrane will subside within a few days. It is also safe and cheap.
However, the discomfort of nicotine withdrawal may cause habituated smokers to
ignore such advice.
Opioid cough depressants, such as codeine, noscapine, pholcodine,
dextromethorfan and the stronger opiates such as morphine, diamorphine and
methadone, effectively suppress the cough reflex. This allows the mucous
membrane to regenerate, although the effect will be less if the lungs continue to be
irritated. The most frequent side effects are constipation, dizziness and sedation. In
high doses they may even depress the respiratory centre. When taken for a long
time tolerance may develop. Sedative antihistamines, such as diphenhydramine,
are used as the cough depressant component of many compound cough
preparations; all tend to cause drowsiness and their efficacy is disputed.
Weighing these facts is the most difficult step, and one where you must make your
own decisions. Although the implications of most data are fairly clear, prescribers
work in varying sociocultural contexts and with different treatment alternatives
available. So the aim of this manual is to teach you how, and not what, to choose,
within the possibilities of your health care systems.
In looking at these two drug groups one has to conclude that there are not many
alternatives available for treating dry cough. In fact, many prescribers would argue
that there is hardly any need for such drugs. This is especially true for the many
cough and cold preparations that are on the market. However, for the sake of this
example, we may conclude that an unproductive, dry cough can be very
inconvenient, and that suppressing such a cough for a few days may have a
beneficial effect. On the grounds of better efficacy we would then prefer a drug
from the group of opioids.
Within this group, codeine is probably the best choice. It is available as tablets and
syrup. Noscapine may have teratogenic side effects; it is not included in the British
National Formulary but is available in other countries. Pholcodine is not available
as tablets. Neither of the two drugs are on the WHO Model List of Essential Drugs.
The stronger opiates are mainly indicated in terminal care.
On the basis of these data we would propose the following first-choice treatment
(your P-treatment). For most patients with a dry cough after a cold, advice will be
effective if it is practical and acceptable for the patient's circumstances. Advice is
certainly safer and cheaper than drugs, but if the patient is not better within a week,
codeine can be prescribed. If the drug treatment is not effective after one week, the
diagnosis should be reconsidered and patient adherence to treatment verified.
Codeine is our P-drug for dry cough. The standard dose for adults would be 3060 mg 3-4 times daily (British National Formulary). Noscapine and pholcodine
could be an alternative.
10
Chapter 1
Conclusion
So, what at first seems just a simple consultation of only a few minutes, in fact
requires a quite complex process of professional analysis. What you should not do
is copy the doctor and memorize that dry cough should be treated with 15 mg
codeine 3 times daily for three days - which is not always true. Instead, build your
clinical practice on the core principles of choosing and giving a treatment, which
have been outlined. The process is summarized below and each step is fully
described in the following chapters.
11
Summary
12
Step 1:
Step 2:
Step 3:
Step 4:
Step 5:
Step 6:
Part 2
13
P
art 2: Selecting your P(ersonal)
drugs
Chapter 2
page
Introduction to P-drugs........................................................................................14
Chapter 3
Example: angina pectoris....................................................................................16
Chapter 4
Guidelines for selecting P-drugs.........................................................................22
Step i:
Step ii:
Step iii:
Step iv:
Step v:
Chapter 5
14
Part 2
15
C hapter 2
Introduction to P-drugs
As a doctor you may see 40 patients per day or more, many of whom need
treatment with a drug. How do you manage to choose the right drug for each patient
in a relatively short time? By using P-drugs! P-drugs are the drugs you have chosen
to prescribe regularly, and with which you have become familiar. They are your
priority choice for given indications.
The P-drug concept is more than just the name of a pharmacological substance, it
also includes the dosage form, dosage schedule and duration of treatment. Pdrugs will differ from country to country, and between doctors, because of varying
availability and cost of drugs, different national formularies and essential drugs
lists, medical culture, and individual interpretation of information. However, the
principle is universally valid. P-drugs enable you to avoid repeated searches for a
good drug in daily practice. And, as you use your P-drugs regularly, you will get to
know their effects and side effects thoroughly, with obvious benefits to the patient.
P-drugs, essential drugs and standard treatment guidelines
You may wonder what the relation is between your set of P-drugs and the WHO
Model List of Essential Drugs or the national list of essential drugs, and existing
standard treament guidelines.
In general, the list of drugs registered for use in the country and the national list of
essential drugs contain many more drugs than you are likely to use regularly. Most
doctors use only 40-60 drugs routinely. It is therefore useful to make your own
selection from these lists, and to make this selection in a rational way. In fact, in
doing so you are preparing your own essential drugs list. Chapter 4 contains
detailed information on the process of selection.
Institutional, national and international (including WHO) standard treatment
guidelines have been developed to deal with the most common conditions, such as
acute respiratory tract infections, diarrhoeal diseases and sexually transmitted
diseases. They are based on good scientific evidence and consensus between
experts. For these reasons they are a valuable tool for rational prescribing and you
should consider them very carefully when choosing your P-drugs. In most cases
you will want to incorporate them in your practice.
P-drugs and P-treatment
16
Chapter 2
Introduction to P-drugs
There is a difference between P-drugs and P-treatment. The key point is that not all
diseases need to be treated with a drug. Not every P-treatment includes a P-drug!
The concept of choosing a P-treatment was already introduced in the previous
chapter. The process of choosing a P-drug is very similar and will be discussed in
the following chapters.
You have final responsibility for your patient's well-being and you cannot pass
this on to others. While you can and should draw on expert opinion and
consensus guidelines, you should always think for yourself. For example, if a
recommended drug is contraindicated for a particular patient, you have to
prescribe another drug. If the standard dosage is inappropriate, you must adapt
it. If you do not agree with a particular drug choice or treatment guideline in
general, prepare your case and defend your choice with the committee that
prepared it. Most guidelines and formularies are updated regularly.
Through developing your own set of P-drugs you will learn how to handle
pharmacological concepts and data. This will enable you to discriminate
between major and minor pharmacological features of a drug, making it much
easier for you to determine its therapeutic value. It will also enable you to
evaluate conflicting information from various sources.
Through compiling your own set of P-drugs you will know the alternatives when
your P-drug choice cannot be used, for example because of serious side
effects or contraindications, or when your P-drug is not available. The same
applies when a recommended standard treatment cannot be used. With the
experience gained in choosing your P-drugs you will more easily be able to
select an alternative drug.
You will regularly receive information on new drugs, new side effects, new
indications, etc. However, remember that the latest and the most expensive
drug is not necessarily the best, the safest or the most cost-effective. If you
cannot effectively evaluate such information you will not be able to update your
list, and you will end up prescribing drugs that are dictated to you by your
colleagues or by sales representatives.
17
C hapter 3
A fictitious brandname
18
Chapter 3
have chosen a drug for an individual patient; in this chapter you will choose a drug
of first choice for a common condition, without a specific patient in mind.
Each of the steps is discussed in detail below, following an example of choosing a
P-drug for angina pectoris.
19
Table 1:
If you do not know enough about pathophysiology of the disease or of the pharmacological sites of action, you
need to update your knowledge. You could start by reviewing your pharmacology notes or textbook; for this
example you should probably also read a few paragraphs on angina pectoris in a medical textbook.
20
Chapter 3
Table 2:
Nitrates
Beta-blockers
Calcium channel blockers
++
+
+
Contractility
++
++
Frequency
++
++
Afterload
++
++
++
21
Table 3:
Safety
Suitability
Nitrates
Pharmacodynamics
Peripheral vasodilatation
Flushing, headaches,
Cardiac failure, hypo-
22
Side effects
Flushing, headaches,
temporary tachycardia
Side effects
Contraindications
Contraindictions
Cardiac failure, hypotension,
raised intracranial pressure
Chapter 3
Tolerance (especially with
constant blood levels)
Nitrate poisoning due to
Anaemia
Pharmacokinetics
High first pass metabolism
Varying absorption in the
alimentary tract (less in
mononitrates)
oromucosal spray
Beta-blockers
Pharmacodynamics
Reduced heart contractility
Reduced heart frequency
Provocation of asthma
Asthma
Bronchoconstriction, muscle
vasoconstriction, inhibited
glycogenolysis
Less vasodilatation in penis
Impotence
Pharmacokinetics
Lipophilicity increases passage
through blood-brain barrier
Drowsiness, decreased
Liver dysfunction
reactions, nightmares
Calcium channel blockers
Pharmacodynamics
Side effects
Contraindications
Side effects
Sinus bradycardia, AV block
Bradycardia, AV block,
Hypotension, congestive heart
failure
Sinus bradycardia, AV block
Cold hand and feet
Raynauds disease
Hypotension, congestive
Hypotension, congestive
Contraindications
sick sinus syndrome
Provocation of asthma
Cold hands and feet
Hypoglycaemia
Impotence
Asthma
Raynauds disease
Diabetes
Drowsiness, decreased
reactions, nightmares
Liver dysfunction
Side effects
Side effects
Contraindications
Contraindictions
Hypotension, congestive
heart failure
Bradycardia, AV block, sick
sinus syndrome
Hypoglycaemia
Diabetes
23
Tachycardia, dizziness,
flushing, hypotension
Congestive heart failure
Sinus bradycardia, AV block
flushing, hypotension
Hypotension
Congestive heart failure
AV block, sick sinus
syndrome
Fast effect dosage forms:
Injection
Congestive heart failure
Congestive heart failure
Tachycardia, dizziness,
Hypotension
Table 4:
Glyceryl trinitrate
Sublingual tab 0.4-1mg
Oral tab 2.6mg, cap 12.5mg
Transdermal patch 1650mg
Isosorbide dinitrate
Sublingual tab 5mg
Oral tab 10-20 mg
Oral tab (retard) 20-40mg
Efficacy
NB: volatile
0.5-30 min
0.5-7 hours
Safety
Suitability
No difference
between
No difference
between
1-24 hours
individual
individual
NB: tolerance
nitrates
nitrates
2-30 min
0.5-4 hours
0.5-10 hours
NB: tolerance
Pentaeritritol tetranitrate
Oral tab 30 mg
1-5 hours
Isosorbide mononitrate
Oral tab 10-40mg
Oral tab/caps (retard)
0.5-4 hours
1-10 hours
Cost/100 ()*
0.29 - 0.59
3.25 - 4 28
42.00
77.00
1.45 - 1.51
1.10 - 2.15
9.52 - 18.95
4.45
5.70 - 13.30
25.00
40.82
NB: tolerance
* Indicative prices only, based on prices given in the British National Formulary of March 1994
After comparing the three groups you may conclude that nitrates are the group of
first choice because, with acceptable efficacy and equal safety, they offer the
advantages of an immediate effect and easy handling by the patient, at no extra
cost.
Chapter 3
Summary
efficacy
safety
suitability
cost
25
Nitrates (tablet)
Beta-blockers (injection)
Calcium channel blockers (injection)
v. Choose a P-drug
Glyceryl trinitrate (tablet)
(spray)
Isosorbide dinitrate (tablet)
Isosorbide mononitrate (tablet)
+
+
+
efficacy
+
+
+
+
safety
++
-
+
-
suitability
+
(+)
+
+
cost
+
Conclusion
Active substance, dosage form: glyceryl trinitrate, sublingual tablet 1 mg
Dosage schedule:
1 tablet as needed; second tablet if pain
persists
Duration:
length of monitoring interval
26
Chapter 4
C hapter 4
The previous chapter gave an example of choosing a P-drug for the treatment of
acute angina pectoris, on the basis of efficacy, safety, suitability and cost. This
chapter presents more general information on each of the five steps.
27
To be able to select the best drug for a given condition, you should study the
pathophysiology of the disease. The more you know about this, the easier it is to
choose a P-drug. Sometimes the physiology of the disease is unknown, while
treatment is possible and necessary. Treating symptoms without really treating the
underlying disease is called symptomatic treatment.
When treating an individual patient you should start by carefully defining the
patients problem (see Chapter 6). When selecting a P-drug you only have to
choose a common problem to start the process.
Chapter 4
Box 2:
Priority should be given to drugs of proven efficacy and safety, in order to meet the needs of the
majority of the people. Unnecessary duplication of drugs and dosage forms should be avoided.
Only those drugs for which adequate scientific data are available from controlled clinical trials
and/or epidemiological studies and for which evidence of performance in general use in a
variety of settings has been obtained, should be selected. Newly released products should only
be included if they have distinct advantages over products currently in use.
Each drug must meet adequate standards of quality, including when necessary bioavailability,
and stability under the anticipated conditions of storage and use.
The international nonproprietary name (INN, generic name) of the drug should be used. This is
the shortened scientific name based on the active ingredient. WHO has the responsibility for
assigning and publishing INNs in English, French, Latin, Russian and Spanish.
The cost of treatment, and especially the cost/benefit ratio of a drug or a dosage form, is a
major selection criterion.
Where two or more drugs appear to be similar, preference should be given to (1) drugs which
have been most thoroughly investigated; (2) drugs with the most favourable pharmacokinetic
properties; and (3) drugs for which reliable local manufacturing facilities exist.
Most essential drugs should be formulated as single compounds. Fixed-ratio combination
products are only acceptable when the dosage of each ingredient meets the requirements of a
defined population group and when the combination has a proven advantage over single
compounds administered separately in therapeutic effect, safety, compliance or cost.
Safety
29
This column summarizes possible side effects and toxic effects. If possible, the
incidence of frequent side effects and the safety margins should be listed. Almost all
side effects are directly linked to the working mechanism of the drug, with the
exception of allergic reactions.
Suitability
Although the final check will only be made with the individual patient, some general
aspects of suitability can be considered when selecting your P-drugs.
Contraindications are related to patient conditions, such as other illnesses which
make it impossible to use a P-drug that is otherwise effective and safe. A change in
the physiology of your patient may influence the dynamics or kinetics of your
P-drug: the required plasma levels may not be reached, or toxic side effects may
occur at normal plasma concentrations. In pregnancy or lactation, the well-being of
the child has to be considered. Interactions with food or other drugs can also
strengthen or diminish the effect of a drug. A convenient dosage form or dosage
schedule can have a strong impact on patient adherence to the treatment.
All these aspects should be taken into account when choosing a P-drug. For
example, in the elderly and children drugs should be in convenient dosage forms,
such as tablets or liquid formulations that are easy to handle. For urinary tract
infections, some of your patients will be pregnant women in whom sulfonamides - a
possible P-drug - are contraindicated in the third trimester. Anticipate this by
choosing a second P-drug for urinary tract infections in this group of patients.
Cost of treatment
The cost of the treatment is always an important criterion, in both developed and
developing countries, and whether it is covered by the state, an insurance company
or directly by the patient. Cost is sometimes difficult to determine for a group of
drugs, but you should always keep it in mind. Certain groups are definitely more
expensive than others. Always look at the total cost of treatment rather than the
cost per unit. The cost arguments really start counting when you choose between
individual drugs.
The final choice between drug groups is your own. It needs practice, but making
this choice on the basis of efficacy, safety, suitability and cost of treatment makes it
easier. Sometimes you will not be able to select only one group, and will have to
take two or three groups on to the next step.
Box 3:
Efficacy: Most prescribers choose drugs on the grounds of efficacy, while side effects are only
taken into consideration after they have been encountered. This means that too many patients
are treated with a drug that is stronger or more sophisticated than necessary (e.g. the use of
wide spectrum antibiotics for simple infections). Another problem is that your P-drug may
score favourably on an aspect that is of little clinical relevance. Sometimes kinetic
characteristics which are clinically of little importance are stressed to promote an expensive
drug while many cheaper alternatives are available.
30
Chapter 4
Safety: Each drug has side effects, even your P-drugs. Side effects are a major hazard in the
industrialized world. It is estimated that up to 10% of hospital admissions are due to adverse
drug reactions. Not all drug induced injury can be prevented, but much of it is caused by
inappropriate selection or dosage of drugs, and you can prevent that. For many side effects,
high risk groups can be distinguished. Often these are exactly the groups of patients you
should always be very careful with: the elderly, children, pregnant women and those with
kidney or liver disease.
Cost: Your ideal choice in terms of efficacy and safety may also be the most expensive drug,
and in case of limited resources this may not be possible. Sometimes you will have to choose
between treating a small number of patients with a very expensive drug, and treating a much
larger number of patients with a drug which is less ideal but still acceptable. This is not an
easy choice to make, but it is one which most prescribers will face. The conditions of health
insurance and reimbursement schemes may also have to be considered. The best drug in
terms of efficacy and safety may not (or only partially) be reimbursed; patients may request
you to prescribe the reimbursed drug, rather than the best one. Where free distribution or
reimbursement schemes do not exist, the patient will have to purchase the drug in a private
pharmacy. When too many drugs are prescribed the patient may only buy some of them, or
insufficient quantities. In these circumstances you should make sure that you only prescribe
drugs that are really necessary, available and affordable. You, the prescriber, should decide
which drugs are the most important, not the patient or the pharmacist.
patient. As a final check you should always compare your selection with existing
treatment guidelines, the national list of essential drugs, and with the WHO Model
List of Essential Drugs, which is reviewed every two years.
Choose a standard dosage schedule
A recommended dosage schedule is based on clinical investigations in a group of
patients. However, this statistical average is not necessarily the optimal schedule
for your individual patient. If age, metabolism, absorption and excretion in your
patient are all average, and if no other diseases or other drugs are involved, the
average dosage is probably adequate. The more your patient varies from this
average, the more likely the need for an individualized dosage schedule.
Recommended dosage schedules for all P-drugs can be found in formularies, desk
references or pharmacology textbooks. In most of these references you will find
rather vague statements such as 2-4 times 30-90 mg per day. What will you
choose in practice?
The best solution is to copy the different dosage schedules into your own formulary.
This will indicate the minimum and maximum limits of the dosage. When dealing
with an individual patient you can make your definitive choice. Some drugs need an
initial loading dose to quickly reach steady state plasma concentration. Others
require a slowly rising dosage schedule, usually to let the patient adapt to the side
effects. Practical aspects of dosage schedules are further discussed in Chapter 8.
32
Chapter 4
Box 4:
33
see the patient again if there is no improvement and so you can prescribe the total
amount at once.
If the duration of treatment is not known, the monitoring interval becomes
important. For example, you may request a patient with newly diagnosed
hypertension to come back in two weeks so that you can monitor blood pressure
and any side effects of the treatment. In this case you would only prescribe for the
two week period. As you get to know the patient better you could extend the
monitoring interval, say, to one month. Three months should be about the
maximum monitoring interval for drug treatment of a chronic disease.
Summary
suitability
cost
suitability
cost
v Choose a P-drug
efficacy
Drug 1
Drug 2
Drug 3
Conclusion:
34
safety
Chapter 5
C
hapter 5
Drink a lot of fluids, eat fruit and high fibre food. Only
go to the toilet when the need is felt. Do not try to pass
stools by force. Reassure patient that nothing points to
serious disease.
Non-drug treatment: Physical exercise.
Drug treatment:
Laxative (your P-drug).
Referral for treatment:
Not indicated.
In many cases advice and non-drug treatment will solve the problem. Because of
tolerance, laxatives are only effective for a short period and may then lead to abuse
and eventually even to electrolyte disturbances. The first treatment plan, your
P-treatment, should therefore be advice; not drugs! If the constipation is severe
(and temporary) your P-drug could be prescribed, e.g. senna tablets for a few days.
If it persists, further examination is needed to exclude other diseases, e.g. a colon
carcinoma.
35
Your advice will prevent further dehydration, but will not cure it, and extra fluids and
ORS will be needed to correct the loss of water and electrolytes. Metronidazole and
antibiotics, such as cotrimoxazole or ampicillin, are not listed in the inventory
because these are not effective in treating watery diarrhoea. Antibiotics are only
indicated for persistent bloody and/or slimy diarrhoea, which is much less common
than watery diarrhoea; metronidazole is mainly used for proven amoebiasis.
Antidiarrhoeal drugs, such as loperamide and diphenoxylate, are not indicated,
especially for children, as they mask the continuing loss of body fluids into the
intestines and may give the false impression that something is being done.
Your P-treatment is therefore: advice to continue feeding and to give extra fluids
(including home made solutions or ORS, depending on the national treatment
guidelines), and to observe the child carefully.
Superficial open wound
The therapeutic objective in the treatment of an open wound is to promote healing
and to prevent infection. The inventory of possible treatments is:
Advice and information:
Non-drug treatment:
Drug treatment:
Referral for treatment:
The wound should be cleaned and dressed, and tetanus prophylaxis should
probably be given. All patients with an open wound should be warned about
possible signs of infection, and to return immediately if these occur. Local
antibiotics are never indicated in wound infections because of their low penetration
and the risk of sensibilization. Systemic antibiotics are rarely indicated for
prophylactic purposes, except in some defined cases such as intestinal surgery.
They will not prevent infection, as permeability into the wound tissue is low, but
they can have serious side effects (allergy, diarrhoea) and may cause resistance.
Your P-treatment for a superficial open wound is therefore to clean and dress the
wound, give antitetanus prophylaxis, and advice on regular wound inspection. No
drugs!
36
Chapter 5
Conclusion
These three examples show that for common complaints the treatment of first
choice often does not include any drugs. Advice and information are often
sufficient, as in the case of constipation. Advice, fluids and rehydration are
essential in the treatment of acute watery diarrhoea, rather than antidiarrhoeals or
antibiotics. Dressing and advice are essential in the case of open wounds, not
antibiotics.
In more serious cases, e.g. persistent constipation, serious dehydration in a small
child or a deep open wound, referral may be the treatment of choice, and not
stronger drugs. Referral can therefore also be your P-treatment, e.g. when no
facilities exist for further examination or treatment.
37
38
Part 3
P
art 3: Treating your patients
Chapter 6
page
Step 1: Define the patients problem...............................................................34
Chapter 7
Step 2: Specify the therapeutic objective.........................................................38
Chapter 8
Step 3: Verify the suitability of your P-drug......................................................40
3A:
3B:
3C:
Chapter 9
Step 4: Write a prescription.............................................................................51
Chapter 10
Step 5: Give information, instructions and warnings .......................................56
Chapter 11
Step 6: Monitor (and stop?) the treatment.......................................................62
39
hapter 6
40
Chapter 7
41
Box 5:
Patient demand
A patient may demand a treatment, or even a specific drug, and this can give you a hard time.
Some patients are difficult to convince that a disease is self-limiting or may not be willing to put
up with even minor physical discomfort. There may be a 'hidden' psycho-social problem, e.g.
long-term use and dependence on benzodiazepine. In some cases it may be difficult to stop the
treatment because psychological or physical dependence on the drugs has been created.
Patient demand for specific drugs occurs most frequently with pain killers, sleeping pills and
other psychotropic drugs, antibiotics, nasal decongestants, cough and cold preparations, and
eye/ear medicines.
The personal characteristics and attitudes of your patients play a very important role. Patients'
expectations are often influenced by the past (the previous doctor always gave a drug), by the
family (the drug that helped Aunt Sally so much), by advertisements to the public, and many
other factors. Although patients do sometimes demand a drug, physicians often assume such a
demand even when it doesn't exist. So a prescription is written because the physician thinks
that the patient thinks... This also applies to the use of injections, or strong drugs in general.
Patient demand for a drug may have several symbolic functions. A prescription legitimizes a
patient's complaint as an illness. It may also fulfill the need that something be done, and
symbolize the care of the physician. It is important to realize that the demand for a drug is much
more than a demand for a chemical substance.
42
Chapter 7
There are no absolute rules about how to deal with patient demand, with the exception of one:
ensure that there is a real dialogue with the patient and give a careful explanation. You need
good communication skills to be a good physician. Find out why the patient thinks as (s)he
does. Make sure you have understood the patient's arguments, and that the patient has
understood you. Never forget that patients are partners in therapy; always take their point of
view seriously and discuss the rationale of your treatment choice. Valid arguments are usually
convincing, provided they are described in understandable terms.
Your enemy when dealing with patient demand is time, i.e. the lack of it. Dialogue and
explanation take time and you often will feel pressed for it. However, in the long run the
investment is worthwhile.
Conclusion
Patients may come to you with a request, a complaint or a question. All may be
related to different problems: a need for reassurance; a sign of underlying disease;
a hidden request for assistance in solving another problem; a side effect of drug
treatment; non-adherence to treatment; or (psychological) dependence on drugs.
Through careful observation, structured history taking, physical examination and
other examinations, you should try to define the patient's real problem. Your
definition (your working diagnosis) may differ from how the patient perceives the
problem. Choosing the appropriate treatment will depend upon this critical step. In
many cases you will not need to prescribe a drug at all.
Summary
Disease or disorder
Sign of underlying disease
Psychological or social problems, anxiety
Side effect of drugs
Refill request (polypharmacy)
Non-adherence to treatment
Request for preventive treatment
Combinations of the above
43
hapter 7
44
Chapter 7
(listlessness, little urine and decreased skin turgor). This dehydration is the most
worrying problem, as she is already slightly undernourished. The therapeutic
objective in this case is therefore (1) to prevent further dehydration and (2) to
rehydrate. Not: to cure the infection! Antibiotics would be ineffective anyway.
Patient 10 (pregnancy)
In Patient 10 you will have recognized Patient 5 who complained of a sore throat
while her real problem was the suspected pregnancy. You will not solve her
problem by prescribing something for her throat. The therapeutic objective depends
on her attitude towards the pregnancy and she will probably need counselling more
than anything else. The therapeutic objective is then to assist her to plan for the
future. This will probably not involve drug treatment for her sore throat. Moreover,
the fact that she is in early pregnancy should stop you from prescribing any drug at
all, unless it is absolutely essential.
Patient 11 (sleeplessness)
In Patient 11 the problem is not which drugs to prescribe, but how to stop
prescribing them. Diazepam is not indicated for long term treatment of
sleeplessness as tolerance quickly develops. It should only be used for short
periods, when strictly necessary. The therapeutic objective in this case is not to
treat the patient's sleeplessness but to avoid a possible dependence on diazepam.
This could be achieved through a gradual and carefully monitored lowering of the
dose to diminish withdrawal symptoms, coupled with more appropriate behavioural
techniques for insomnia, which should lead to eventual cessation of the drug.
Patient 12 (tiredness)
In Patient 12 there is no clear cause for the tiredness and it is therefore difficult to
make a rational treatment plan. Having excluded anaemia you may guess that as a
young mother with small children and perhaps a job outside the home, she is
chronically overworked. The therapeutic objective is therefore to help her reduce
physical and emotional overload. To achieve this it may be necessary to involve
other members of the family. This is a good example of the need for non-drug
therapy. Vitamins will not help, and would only act as a placebo. In fact, they would
probably act as a placebo for yourself as well, creating the false impression that
something is being done.
Conclusion
As you can see, in some cases the therapeutic objective will be straightforward: the
treatment of an infection or a condition. Sometimes the picture will be less clear, as
in the patient with unexplained tiredness. It may even be misleading, as in the
student with the sore throat. You will have noticed that specifying the therapeutic
objective is a good way to structure your thinking. It forces you to concentrate on
the real problem, which limits the number of treatment possibilities and so makes
your final choice much easier.
Specifying your therapeutic objective will prevent a lot of unnecessary drug use. It
should stop you from treating two diseases at the same time if you cannot choose
between them, like prescribing antimalarial drugs and antibiotics in case of fever, or
antifungal and corticosteroid skin ointment when you can not choose between a
fungus and eczema.
Specifying your therapeutic objective will also help you avoid unnecessary
prophylactic prescribing, for example, the use of antibiotics to prevent wound
infection, which is a very common cause of irrational drug use.
45
It is a good idea to discuss your therapeutic objective with the patient before you
start the treatment. This may reveal that (s)he has quite different views about
illness causation, diagnosis and treatment. It also makes the patient an informed
partner in the therapy and improves adherence to treatment.
46
Chapter 8
hapter 8
47
48
Chapter 8
Step 3A: Are the active substance and dosage form suitable for this patient?
Effectiveness
We assume that all your P-drugs have already been selected on the basis of
efficacy. However, you should now verify that the drug will also be effective in this
individual patient. For this purpose you have to review whether the active
substance is likely to achieve the therapeutic objective, and whether the dosage
form is convenient for the patient. Convenience contributes to patient adherence
to the treatment, and therefore to effectiveness. Complicated dosage forms or
packages and special storage requirements can be major obstacles for some
patients.
Safety
Table 5:
High risk factors/
groups
Pregnancy
Lactation
Children
Elderly
Renal failure
Hepatic failure
History of drug
allergy
Other diseases
Other medication
This is a cheap and convenient way of giving a drug to a small child. However, it should not be done with
capsules nor with special tablets such as sugarcoated or slow-release preparations.
50
Chapter 8
Step 3B: Is the standard dosage schedule suitable for this patient?
The aim of a dosage schedule is to maintain the plasma level of the drug within the
therapeutic window. As in the previous step, the dosage schedule should be
effective and safe for the individual patient. There are two main reasons why a
standard dosage schedule may have to be adapted. The window and/or plasma
curve may have changed, or the dosage schedule is inconvenient to the patient. If
you are not familiar with the concept of the therapeutic window and the plasma
concentration-time curve, read Annex 1.
Exercise: patients 17-20
Review for each of the following cases whether the dosage
schedule is suitable (effective, safe) for the patient. Adapt the
schedule where necessary. The cases are discussed below.
Patient 17:
Woman, 43 years. History of insulin dependent diabetes for 26
years. Stable on treatment with two daily doses of neutral insulin,
20 IU and 30 IU. Recently mild hypertension was diagnosed, and
diet and general advice have not been sufficiently effective. You
would like to treat this condition with a beta-blocker. Your P-drug
is atenolol 50 mg once daily.
Patient 18:
Man, 45 years. Terminal lung cancer. He has lost 3 kg during the
last week. You have been treating his pain successfully with your
P-drug, oral morphine solution, 10 mg twice daily. Now he
complains that the pain is getting worse.
Patient 19:
Woman, 50 years. Chronic rheumatic disease, treated with your
P-drug, indometacin, 3 times 50 mg daily plus a 50 mg
suppository at night. She complains of pain early in the morning.
Patient 18 again, after one week:
He has lost another 6 kg, and looks very ill. He was on oral
morphine solution, 15 mg twice daily, to which he had responded
well. However, he has become very drowsy and has to be woken
up to hear what you say. He has no pain.
Patient 20:
Man, 73 years. Has suffered from depression for two years, after
the death of his wife. You want to prescribe an antidepressant
drug. Your P-drug is amitriptyline, 25 mg daily initially, followed by
a slowly rising dose till the drug is effective (with a maximum of
150 mg per day).
51
52
Chapter 8
In Patient 19 (pain at night) the plasma concentration of indometacin probably falls below
the therapeutic window early in the morning (see Figure 2). Any change in medication
should therefore aim at increasing the plasma level in that period. You could advise her to
take the evening dose later, or to set the alarm in the night to take an extra tablet. You could
also increase the strength of the evening suppository to 100 mg, while decreasing her first
morning tablet to 25 mg.
Table 6:
Relation between ADME
factors and plasma
concentration
Plasma concentration
curve will drop if:
Absorption is low
Distribution is high
Metabolism is high
Excretion is high
Plasma concentration
curve will rise if:
Absorption is high
Distribution is low
Metabolism is low
Excretion is low
Four factors determine the course of the concentration curve, usually called ADME-factors:
Absorption, Distribution, Metabolism and Excretion. You always have to check whether ADMEfactors in your patient are different compared to average patients. If so, you have to
determine what this will do to the plasma curve. Any change in ADME-factors influences
plasma concentration (see Table 6).
How can you define the position of the plasma curve in an individual patient? The plasma
concentration can be measured by laboratory investigations, but in many settings this is not
possible and it may be expensive. More important, each measurement represents only one
point of the curve and is difficult to interpret without special training and experience. More
measurements are expensive and may be stressful to the patient, especially in an outpatient
setting. It is simpler to look for clinical signs of toxic effects. These are often easy to detect
by history taking and clinical investigation.
53
Decreasing the daily dose is usually easy. You can reduce the number of tablets, or
divide them into halves. Beware of antibiotics, because some may need high peaks
in plasma concentration to be effective. In that case you should reduce the
frequency, not the dose.
54
Chapter 8
Increasing the daily dose is a little more complicated. Doubling the dose while
maintaining the same frequency not only doubles the mean plasma level, but also
increases the fluctuations on both sides of the curve. In drugs with a narrow safety
margin the curve may now fluctuate outside the therapeutic window. The safest
way to prevent this is to raise the frequency of dosage. However, few patients like
taking drugs 12 times a day and a compromise has to be found to maintain
adherence to treatment. After changing the daily dose it takes four times the halflife of the drug to reach the new steady state. Table 7 lists those drugs for which it
is advisable to start treatment with a slowly rising dosage schedule.
55
Table 7:
Step 3C: Is the standard duration of treatment suitable for this patient?
Many doctors not only prescribe too much of a drug for too long, but also frequently
too little of a drug for too short a period. In one study about 10% of patients on
benzodiazepines received them for a year or longer. Another study showed that
16% of outpatients with cancer still suffered from pain because doctors were afraid
to prescribe morphine for a long period. They mistook tolerance for addiction. The
duration of the treatment and the quantity of drugs prescribed should also be
effective and safe for the individual patient.
Overprescribing leads to many undesired effects. The patient receives
unnecessary treatment, or drugs may lose some of their potency. Unnecessary
side effects may occur. The quantity available may enable the patient to overdose.
Drug dependence and addiction may occur. Some reconstituted drugs, such as eye
drops and antibiotic syrups, may become contaminated. It may be very
inconvenient for the patient to take so many drugs. Last, but not least, valuable and
often scarce resources are wasted.
Underprescribing is also serious. The treatment is not effective, and more
aggressive or expensive treatment may be needed later. Prophylaxis may be
ineffective, resulting in serious disease, e.g. malaria. Most patients will find it
inconvenient to return for further treatment. Money spent on ineffective treatment is
money wasted.
Exercise: patients 21-28
For each of the following cases verify whether the duration of
treatment and total quantity of the drugs are suitable (effective,
safe). In all cases you may assume that the drugs are your
P-drugs.
Patient 21:
Woman, 56 years. Newly diagnosed depression. R/amitriptyline
25 mg, one tablet daily at night, give 30 tablets.
Patient 22:
Child, 6 years. Giardiasis with persistent diarrhoea. R/metronidazole
200 mg/5 ml oral suspension, 5 ml three times daily, give 105 ml.
56
Chapter 8
Patient 23:
Man, 18 years. Dry cough after a cold. R/codeine 30 mg, 1 tablet
three times daily, give 60 tablets.
Patient 24:
Woman, 62 years. Angina pectoris, waiting for referral to a
specialist. R/glyceryl trinitrate 5 mg, as necessary 1 tablet
sublingual, give 60 tablets.
Patient 25:
Man, 44 years. Sleeplessness. Comes for a refill, R/diazepam 5
mg, 1 tablet before sleeping, give 60 tablets.
Patient 26:
Girl, 15 years. Needs malaria prophylaxis for a two week trip to
Ghana. R/mefloquine 250 mg, 1 tablet weekly, give 7 tablets; start
one week before departure and continue four weeks after return.
Patient 27:
Boy, 14 years. Acute conjunctivitis. R/tetracycline 0.5% eye drops,
first 3 days every hour 1 drop, then 2 drops every six hours, give
10 ml.
Patient 28:
Woman, 24 years. Feels weak and looks a bit anaemic. No Hb
result available. R/ferrous sulfate 60 mg tablets, 1 tablet three
times daily, give 30 tablets.
Patient 21 (depression)
A dose of 25 mg per day is probably insufficient to treat her depression. Although
she can start with such a low dose for a few days or a week, mainly to get used to
side effects of the drug, she may finally need 100-150 mg per day. With 30 tablets
the quantity is sufficient for one month, if the dosage is not changed before that
time. But is it safe? At the beginning of the treatment the effect and side effects
cannot be foreseen. And if the treatment has to be stopped, the remaining drugs
are wasted. The risk of suicide also has to be considered: depressive patients are
more liable to commit suicide in the initial stages of treatment when they become
more active because of the drug, but still feel depressed. For these reasons 30
tablets are not suitable. It would be better to start with 10 tablets, for the first week
or so. If she reacts well you should increase the dose.
Patient 22 (giardiasis)
With most infections time is needed to kill the microbes, and short treatments may
not be effective. However, after prolonged treatment the micro-organisms may
develop resistance and more side effects will occur. In this patient the treatment is
both effective and safe. Giardiasis with persistent diarrhoea needs to be treated for
one week, and 105 ml is exactly enough for that period. Maybe it is even too exact.
Most pharmacists do not want to dispense quantities such as 105 ml or 49 tablets.
They prefer rounded figures, such as 100 ml or 50 tablets, because calculating is
easier and drugs are usually stocked or packed in such quantities.
57
Box 6:
In long-term treatment, patient adherence to treatment can be a problem. Often the patient
stops taking the drug when the symptoms have disappeared or if side effects occur. For patients
with chronic conditions repeat prescriptions are often prepared by the receptionist or assistant
and just signed by the physician. This may be convenient for doctor and patient but it has
certain risks, as the process of renewal becomes a routine, rather than a conscious act.
Automatic refills are one of the main reasons for overprescribing in industrialized countries,
especially in chronic conditions. When patients live far away, convenience may lead to
prescriptions for longer periods. This may also result in over prescribing. You should see your
patients on long-term treatment at least four times per year.
Chapter 8
Patient 28 (weakness)
Did you notice that this is a typical example of a prescription without a clear
therapeutic objective? If the diagnosis is uncertain, the Hb should be measured. If
the patient is really anaemic she will need much more iron than the ten days given
here. She will probably need treatment for several weeks or months, with regular
Hb measurements in between.
Conclusion
Verifying whether your P-drug is also suitable for the individual patient in front of
you is probably the most important step in the process of rational prescribing. It
also applies if you are working in an environment in which essential drugs lists,
formularies and treatment guidelines exist. In daily practice, adapting the dosage
schedule to the individual patient is probably the most common change that you will
make.
Summary
STEP 3:
3A
3B
3C
If necessary, change the dosage form, the dosage schedule or the duration of
treatment.
In some cases it is better to change to another P-drug.
59
C
Cartoon 3
hapter 9
Information on a prescription
There is no global standard for prescriptions and every country has its own
regulations. Do you know the legal requirements in your own country? The most
important requirement is that the prescription be clear. It should be legible and
indicate precisely what should be given. Few prescriptions are still written in Latin;
the local language is preferred. If you include the following information, not much
can go wrong.
Name and address of the prescriber, with telephone number (if possible)
60
Chapter 9
This is usually pre-printed on the form. If the pharmacist has any questions about
the prescription (s)he can easily contact the prescriber.
Date of the prescription
In many countries the validity of a prescription has no time limit, but in some
countries pharmacists do not give out drugs on prescriptions older than three to six
months. You should check the rules in your own country.
Name and strength of the drug
R/ (not Rx) is derived from Recipe (Latin for take). After R/ you should write the
name of the drug and the strength. It is strongly recommended to use the generic
(nonproprietary) name. This facilitates education and information. It means that you
do not express an opinion about a particular brand of the drug, which may be
unnecessarily expensive for the patient. It also enables the pharmacist to maintain
a more limited stock of drugs, or dispense the cheapest drug. However, if there is a
particular reason to prescribe a special brand, the trade name can be added. Some
countries allow generic substitution by the pharmacist and require the addition Do
not substitute or Dispense as written if that brand, and no other, is to be
dispensed.
The strength of the drug indicates how many milligrams each tablet, suppository, or
milliliter of fluid should contain. Internationally accepted abbreviations should be
used: g for gram, ml for milliliter. Try to avoid decimals and, where necessary, write
words in full to avoid misunderstanding. For example, write levothyroxin 50
micrograms, not 0.050 milligrams or 50 ug. Badly handwritten prescriptions can
lead to mistakes, and it is the legal duty of the doctor to write legibly (Box 7). In
prescriptions for controlled drugs or those with a potential for abuse it is safer to
write the strength and total amount in words, to prevent tampering. Instructions for
use must be clear and the maximum daily dose mentioned. Use indelible ink.
Box 7:
Doctors are legally obliged to write clearly, as emphasized in the UK Court of Appeal ruling in
the following case. A doctor had written a prescription for Amoxil tablets (amoxicillin). The
pharmacist misread this and dispensed Daonil (glibenclamide) instead. The patient was not a
diabetic and suffered permanent brain damage as a result of taking the drug.
The court indicated that a doctor owed a duty of care to a patient to write a prescription clearly
and with sufficient legibility to allow for possible mistakes by a busy pharmacist. The court
concluded that the word Amoxil on the prescription could have been read as Daonil. It found
that the doctor had been in breach of his duty to write clearly and had been negligent. The
court concluded that the doctor's negligence had contributed to the negligence of the
pharmacist, although the greater proportion of the responsibility (75%) lay with the pharmacist.
On appeal the doctor argued that the word on the prescription standing on its own could
reasonably have been read incorrectly but that various other aspects of the prescription should
have alerted the pharmacist. The strength prescribed was appropriate for Amoxil but not for
Daonil; the prescription was for Amoxil to be taken three times a day while Daonil was usually
taken once a day; the prescription was for only seven days' treatment, which was unlikely for
Daonil; and finally, all prescriptions of drugs for diabetes were free under the National Health
61
Service but the patient did not claim free treatment for the drug. All of these factors should
have raised doubts in the mind of the pharmacist and as a result he should have contacted the
doctor. Therefore, the chain of causation from the doctor's bad handwriting to the eventual
injury was broken.
This argument was rejected in the Court of Appeal. The implications of this ruling are that
doctors are under a legal duty of care to write clearly, that is with sufficient legibility to allow for
mistakes by others. When illegible handwriting results in a breach of that duty, causing
personal injury, then the courts will be prepared to punish the careless by awarding sufficient
damages. Liability does not end when the prescription leaves the doctor's consulting room. It
may also be a cause of the negligence of others.
Source: J R Coll Gen Pract, 1989: 347-8
Box 8:
Incomplete labels
The label on the drug package is very important for the patient as a reminder of the
instructions for use. In many cases, however, labels are incomplete. An analysis of 1533
(=100%) labels showed:
No label or illegible
Quantity not recorded
No directions, or only as before/as directed
No date
1.%
50.%
26.%
14.%
The data listed above are the core of every prescription. Additional information may
be added, such as the type of health insurance the patient has. The layout of the
prescription form and the period of validity may vary between countries. The
62
Chapter 9
of
the
following
patients.
Patient 29:
Boy, 5 years. Pneumonia with greenish sputum. Your P-drug is
amoxicillin syrup.
Patient 30:
Woman, 70 years. Moderate congestive cardiac failure. For
several years on digoxin 0.25 mg 1 tablet daily. She phones to
ask for a repeat prescription. As you have not seen her for some
time you ask her to call. During the visit she complains of slight
nausea and loss of appetite. No vomiting or diarrhoea. You
suspect side effects of digoxin, and call her cardiologist. As she
has an appointment with him next week, and he is very busy, he
advises you to halve the dose until then.
Patient 31:
Woman, 22 years. New patient. Migraine with increasingly
frequent vomiting. Paracetamol no longer effective during attacks.
You explain to her that the paracetamol does not work because
she vomits the drug before it is absorbed. You prescribe
paracetamol plus an anti-emetic suppository, metoclopramide,
which she should take first, and wait 20-30 minutes before taking
the paracetamol.
Patient 32:
Man, 53 years. Terminal stage of pancreatic cancer, confined to
bed at home. You visit him once a week. Today his wife calls and
asks you to come earlier because he is in considerable pain. You
go immediately. He has slept badly over the weekend and regular
painkillers are not working. Together you decide to try morphine
for a week. Making sure not to underdose him, you start with 10
mg every six hours, with 20 mg at night. He also has non-insulin
dependent diabetes, so you add a refill for his tolbutamide.
There is nothing wrong with any of the four prescriptions (Figures 6, 7, 8 and 9).
However, a few remarks can be made. Repeat prescriptions, such as the one for
patient 30, are permitted. Many prescriptions are like that. But they also need your
full attention. Do not write a repeat prescription automatically! Check how many
times it has been repeated. Is it still effective? It is still safe? Does it still meet the
original needs?
For the opiate for patient 32, the strength and the total amount have been written in
words so they cannot easily be altered. The instructions are detailed and the
maximum daily dose is mentioned. In some countries it is mandatory to write an
opiate prescription on a separate prescription sheet.
Summary
63
date
Dr B. Who
Farmstreet 12
Kirkville
tel. 3876
R/
date
Ms/Mr
address:
age:
Ms/Mr
address:
age:
64
Chapter 10
hapter 10
65
Woman, 59 years. She is taking drugs for congestive heart failure and
hypertension. She also has a newly diagnosed gastric ulcer, for which she has
been prescribed another drug. As the doctor is explaining why she needs the new
drug and how she should take it, her thoughts are drifting away. The doctor's voice
sinks into the background as she starts worrying about the new illness, afraid of the
consequences and how she will remember to take all these drugs. The doctor
doesn't notice the loss of attention, doesn't encourage a dialogue but just keeps on
talking and talking. In the pharmacy her thoughts are still wandering off even when
the pharmacist is explaining how to take the drug. When she gets home she finds
her daughter waiting to hear the results of her visit to the doctor. Without telling her
the diagnosis she talks about her worry: how to cope with all these different drugs.
Finally her daughter reassures her and says that she will help her to take the drugs
correctly.
On average, 50% of patients do not take prescribed drugs correctly, take them
irregularly, or not at all. The most common reasons are that symptoms have
ceased, side effects have occurred, the drug is not perceived as effective, or the
dosage schedule is complicated for patients, particularly the elderly. Non adherence
to treatment may have no serious consequences. For example, irregular doses of a
thiazide still give the same result, as the drug has a long half-life and a flat doseresponse curve. But drugs with a short half-life (e.g. fenytoin) or a narrow
therapeutic margin (e.g. theophylline) may become ineffective or toxic if taken
irregularly.
Patient adherence to treatment can be improved in three ways: prescribe a well
chosen drug treatment; create a good doctor-patient relationship; take time to give
the necessary information, instructions and warnings. A number of patient aids are
discussed in Box 9. A well chosen drug treatment consists of as few drugs as
possible (preferably only one), with rapid action, with as few side effects as
possible, in an appropriate dosage form, with a simple dosage schedule (one or
two times daily), and for the shortest possible duration.
66
Chapter 10
Box 9:
Patient leaflets
Patient leaflets reinforce the information given by the prescriber and pharmacist. The text
should be in clear, common language and in easily legible print.
Pictorials and short descriptions
If the patient cannot read, try pictorials. If they are not available, make pictorials or short
descriptions for your own P-drugs, and photocopy them.
Day calendar
A day calendar indicates which drug should be taken at different times of the day. It can use
words or pictorials: a low sun on the left for morning, a high sun for midday, a sinking sun for
the end of the day and a moon for the night.
Drug passport
A small book or leaflet with an overview of the different drugs that the patient is using,
including recommended dosages.
Dosage box
The dosage box is becoming popular in industrialized countries. It is especially helpful when
many different drugs are used at different times during the day. The box has compartments for
the different times per day (usually four), spread over seven days. It can then be refilled each
week. If cost is a problem, the box can be made locally from cardboard. In tropical countries a
cool and clean place to store the box will be necessary.
Even if the patient aids described here don't exist in your country, with creativity you can often
find your own solutions. The important thing is to give your patients the information and tools
they need to use drugs appropriately.
The six points listed below summarize the minimum information that should be
given to the patient.
1.
2.
Side effects
Which side effects may occur
How to recognize them
How long they will continue
How serious they are
What action to take
3.
Instructions
How the drug should be taken
When it should be taken
How long the treatment should continue
67
Warnings
When the drug should not be taken
What is the maximum dose
Why the full treatment course should be taken
5.
Future consultations
When to come back (or not)
In what circumstances to come earlier
What information the doctor will need at the next appointment
6.
Everything clear?
Ask the patient whether everything is understood
Ask the patient to repeat the most important information
Ask whether the patient has any more questions
This may seem a long list to go through with each patient. You may think that there
is not enough time; that the patient can read the package insert with the medicine;
that the pharmacist or dispenser should give this information; or that too much
information on side effects could even decrease adherence to treatment. Yet it is
the prime responsibility of the doctor to ensure that the treatment is understood by
the patient, and this responsibility cannot be shifted to the pharmacist or a package
insert. Maybe not all side effects have to be mentioned, but you should at least
warn your patients of the most dangerous or inconvenient side effects. Having too
many patients is never accepted by a court of law as a valid excuse for not
informing and instructing a patient correctly.
essential hypertension.
Patient 37:
Boy, 5 years. Pneumonia. R/amoxicillin syrup, 5 ml (= 250 mg)
three times daily.
Patient 38:
68
Chapter 10
69
Beta blocker
ATENOLOL
* DOSAGE
Hypertension: start with 50 mg in the morning. Average: 50-100 mg per day.
Angina pectoris: 100 mg per day in 1-2 doses
Adjust to each patient individually, start as low as possible. Raise the dose after 2
weeks, if needed.
* WHAT TO TELL THE PATIENT
Information
Hypertension: drug decreases blood pressure, patient will usually not notice any
effect. Drug will prevent complications of high blood pressure (angina, heart attack,
cerebrovascular accident).
Angina pectoris: decreases blood pressure, prevents the heart from working too
hard, preventing chest pain.
Side effects: hardly any, sometimes slight sedation.
Instructions
Take the drug .. times per day, for .. days
Warnings
Angina pectoris: do not suddenly stop taking the drug.
Next appointment
Hypertension: one week.
Angina pectoris: within one month, earlier if attacks occur more frequently, or
become more severe.
* FOLLOW-UP
Hypertension: during first few months pulse and blood pressure should be checked
weekly. Try to decrease dosage after three months. Higher dosages do not increase
therapeutic effect, but may increase side effects. Try to stop treatment from time to
time.
Angina pectoris: in case frequency or severity of the attacks increase, more
diagnostic tests or other treatment are needed. Try to stop drug treatment from time
to time.
Summary
70
Chapter 10
STEP 5:
1.
2.
Side effects
Which side effects may occur; how to recognize them; how long will they
remain; how serious they are; what to do if they occur;
3.
Instructions
When to take; how to take; how to store; how long to continue the
treatment; what to do in case of problems;
4.
Warnings
What not to do (driving, machinery); maximum dose (toxic drugs); need
to continue treatment (antibiotics);
5.
Next appointment
When to come back (or not); when to come earlier; what to do with leftover drugs; what information will be needed;
6.
Everything clear?
Everything understood; repeat the information; any more questions.
71
hapter 11
72
Chapter 11
If the disease is cured, the treatment can be stopped. 4 If the disease is not yet
Table 8:
Some examples of drugs in
which a slow reduction in dose
should be considered
Amphetamines
Antiepileptics
Antidepressants
Antipsychotics
Cardiovascular drugs
clonidine
methyldopa
beta-blockers
vasodilators
Corticosteroids
Hypnotics/sedatives
benzodiazepines
barbiturates
Opiates
cured or chronic, and the treatment is effective and without side effects, it can be
continued. If serious side effects have occurred you should reconsider your
selected drug and dosage schedule, and check whether the patient was correctly
instructed. Many side effects are dose dependent, so you may try to lower the dose
before changing to another drug.
Except in cases in which a standard duration of treatment is crucial, such as with most antibiotics.
73
74
Chapter 11
this can lead patients to take more than the recommended dose. You should
explain this to the patient and also tell him that the nature of the sleep induced by
such drugs is not the same as normal sleep, but the result of suppressed brain
activity. Encourage him to try to return to natural sleep patterns; possibly a warm
bath or a hot milk drink will help to promote relaxation before bedtime. It may also
help to encourage him to express his feelings about his loss; acting as a
sympathetic listener is probably your major therapeutic role in this case, rather than
prescribing more drugs. In this case the drug can be stopped at once because it
was only used for one week. This cannot be done when patients have taken
benzodiazepines for longer periods of time.
75
Summary
STEP 6:
76
Chapter 11
77
P
art 4: Keeping up-to-date
Chapter 12
page
How to keep up-to-date about drugs..................................................................68
Make an inventory of available information...............................................68
Choose between sources of information...................................................74
Efficient reading........................................................................................74
Conclusion................................................................................................75
78
Part 4
Keeping up-to-date
79
hapter 12
80
Chapter 12
use in that country, region, district or hospital. In many countries drug formularies
are also developed for health insurance programmes, listing the products that are
reimbursed. Drug formularies are usually drug-centred. Their value is enhanced if
they contain comparisons between drugs, evaluations and cost information, but
that is often not the case. The excellent BNF has already been mentioned. Try to
get your own copy, even if it is not the most recent one. It fits well in your pocket.
Drug bulletins
These periodicals promote rational drug therapy and appear at frequent intervals,
ranging from weekly to quarterly. Independent drug bulletins, i.e. non-industry
sponsored, provide impartial assessments of drugs and practical recommendations, based on a comparison between treatment alternatives.
Drug bulletins can be a critical source of information in helping prescribers to
determine the relative merits of new drugs and in keeping up-to-date. Drug bulletins
can have a variety of sponsors, such as government agencies, professional bodies,
university departments, philanthropic foundations and consumer organizations.
They are published in many countries, are often free of charge, and are highly
respected because of their unbiased information. Examples in English are: Drug
and Therapeutics Bulletin (UK), Medical Letter (USA) and Australian Prescriber
(Australia). A good independent drug bulletin in French is Prescrire; it is not free of
charge.
National drug bulletins are appearing in an increasing number of developing
countries, which include Bolivia, Cameroon, Malawi, the Philippines and Zimbabwe.
The main advantages of national drug bulletins are that they can select topics of
national relevance and use the national language.
Medical journals
Some medical journals are general, such as The Lancet, the New England Journal
of Medicine or the British Medical Journal; others are more specialized. Most
countries have their own national equivalents. Both types contain much information
of relevance to prescribers. The general journals regularly publish review articles
on treatment. The specialized journals include more detailed information on drug
therapy for specific diseases.
Good medical journals are 'peer reviewed', that is, all articles are sent for
independent expert review prior to publication. You can usually check whether
journals meet this important criterion by reading the published instructions for
submission of articles.
Some journals are not independent. They are usually glossy and often present
information in an easily digestible format. They can be characterized as: free of
charge, carrying more advertisements than text, not published by professional
bodies, not publishing original work, variably subject to peer review, and deficient in
critical editorials and correspondence. In the industrialized world they are promoted
to the physician as a 'way to save time'. In fact reading them is a loss of time, which
is why they are commonly referred to as 'throwaways'. Also be careful with journal
supplements. They sometimes report on commercially sponsored conferences; in
fact, the whole supplement may be sponsored.
So don't assume that because a review article or research study appears in print
that it is necessarily good science. Thousands of 'medical' journals are published
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Chapter 12
and they vary enormously in quality. Only a relatively small proportion publish
scientifically validated, peer reviewed articles. If in doubt about the scientific value
of a journal, verify its sponsors, consult senior colleagues, and check whether it is
included in the Index Medicus, which covers all major reputable journals.
Verbal information
Another way to keep up-to-date is by drawing on the knowledge of specialists,
colleagues, pharmacists or pharmacologists, informally or in a more structured way
through postgraduate training courses or participation in therapeutic committees.
Community based committees typically consist of general practitioners and one or
more pharmacists. In a hospital setting they may include several specialists, a
clinical pharmacologist and/or a clinical pharmacist. Such committees meet
regularly to discuss aspects of drug treatment. In some cases they establish local
formularies and follow up on their use. Using a clinical specialist as the first source
of information may not be ideal when you are a primary health care physician. In
many instances the knowledge of specialists may not really be applicable to your
patients. Some of the diagnostic tools or more sophisticated drugs may not be
available, or needed, at that level of care.
Drug information centres
Some countries have drug information centres, often linked to poison information
centres. Health workers, and sometimes the general public, can call and get help
with questions concerning drug use, intoxications, etc. Modern informatics, such as
on-line computers and CD-ROM, have dramatically improved access to large
volumes of data. Many major reference data bases, such as Martindale and
Meylers Side Effects of Drugs, are now directly accessible through international
electronic networks. When drug information centres are run by the pharmaceutical
department of the ministry of health, the information is usually drug focused.
Centres located in teaching hospitals or universities may be more drug problem or
clinically oriented.
Computerized information
Computerized drug information systems that maintain medication profiles for every
patient have been developed. Some of these systems are quite sophisticated and
include modules to identify drug interactions or contraindications. Some systems
include a formulary for every diagnosis, presenting the prescriber with a number of
indicated drugs from which to choose, including dosage schedule and quantity.
Prescribers can also store their own formulary in the computer. If this is done,
regular updating is needed using the sources of information described here. In
many parts of the world access to the hardware and software needed for this
technology will remain beyond the reach of individual prescribers. In countries
where such technology is easily accessible it can make a useful contribution to
prescribing practice. However, such systems cannot replace informed prescriber
choice, tailored to meet the needs of individual patients.
Pharmaceutical industry sources of information
Information from the pharmaceutical industry is usually readily available through all
channels of communication: verbal, written and computerized. Industry promotion
budgets are large and the information produced is invariably attractive and easy to
digest. However, commercial sources of information often emphasize only the
positive aspects of products and overlook or give little coverage to the negative
83
Usually the pharmaceutical industry uses a 'multi-track' approach. This means that
the information is provided through a number of media: medical representatives
(detail men/women), stands at professional meetings, advertising in journals and
direct mailing.
From industry's point of view, medical representatives are usually very effective in
promoting drug products, and much more effective than mailings alone. Often over
50% of the promotional budget of pharmaceutical companies in industrialized
countries is spent on representatives. Studies from a number of countries have
shown that over 90% of physicians see representatives, and a substantial
percentage rely heavily on them as sources of information about therapeutics.
However, the literature also shows that the more reliant doctors are on commercial
sources of information only, the less adequate they are as prescribers.
In deciding whether or not to use the services of drug representatives to update
your knowledge on drugs, you should compare the potential benefits with those of
spending the same time reading objective comparative information.
If you do decide to see representatives, there are ways to optimize the time you
spend with them. Take control of the discussion at the outset so that you get the
information you need about the drug, including its cost. If your country has a health
insurance scheme, check whether the drug is included in the list of reimbursable
products. Early on in the discussion ask the representative to give you a copy of
the officially registered drug information (data sheet) on the product under
discussion, and during the presentation compare the verbal statements with those
in the official text. In particular look at side effects and contraindications. This
approach will also help you to memorize key information about the drug.
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Chapter 12
Always ask for copies of the published references on efficacy and safety. Even
before reading these, the quality of the journals in which they appear will be a
strong indication of the likely quality of the study. You should know that the majority
of newly marketed drugs do not represent true therapeutic advances but are what
is known as me too products. In other words, they are very similar in chemical
composition and action to other products on the market. The difference is usually in
price; the most recently marketed drug is usually the most expensive! Seeing
medical representatives can be useful to learn what is new, but the information
should always be verified and compared with impartial, comparative sources.
Drug information from commercial sources is also issued as news reports, and as
scientific articles in professional journals. Industry is also a major sponsor of
scientific conferences and symposia. The line between objective and promotional
information is not always clear. A number of countries and professional
associations are tightening regulations controlling drug promotion to tackle this
problem. Some journals now require that any sponsorship from the pharmaceutical
industry should be mentioned in the article.
As mentioned above and as studies show, it is not good practice to use only
commercial information to keep up-to-date. Although it may seem an easy way to
gather information, this source is often biased towards certain products and is likely
to result in irrational prescribing. This is particularly true for countries without an
effective regulatory agency, because more drugs of sometimes doubtful efficacy
may be available and there may be little control on the contents of data-sheets and
advertisements.
WHO has issued Ethical Criteria for Medicinal Drug Promotion which contain global
guidelines for promotional activities. The International Federation of
Pharmaceutical Manufacturers Associations also has a code of pharmaceutical
marketing practices. In several countries national guidelines exist as well. Most
guidelines specify that the promotional information should be accurate, complete
and in good taste. It is a very good exercise to compare a number of drug
advertisements with the national or global criteria. Most guidelines also cover the
use of samples and gifts, participation in promotional conferences and clinical trials,
etc.
If you do use commercial information follow these ground rules. First, look for more
information than advertisements contain. Second, look or ask for references, and
check their quality. Only references in well established peer reviewed journals
should be taken seriously. Then check the quality of the research methodology on
which the conclusions are based. Third, check what your colleagues, and
preferably a specialist in the field, know about the drug. Finally, always collect data
from unbiased sources before actually using the drug. Do not start by using free
samples on a few patients or family members, and do not base your conclusions
on the treatment of a few patients!
Yet commercial information is sometimes helpful in a general sense, especially to
know of new developments. However, comparative information from drug bulletins
or therapeutic reviews is absolutely essential to help you evaluate the new drug in
relation to existing treatments, and to decide whether you wish to include it in your
personal formulary.
85
Efficient reading
Articles
Many prescribers have a problem in reading everything they would like. The
reasons are lack of time and - in industrialized countries - the sheer volume of
materials mailed to them. It's wise to adopt a strategy to use your time as efficiently
as possible.
You can save time when reading clinical journals by identifying at an early stage
articles which are worth reading, through the steps listed below.
1. Look at the title to determine if it appears interesting or useful to you. If not,
move on to the next article.
2. Review the authors. The experienced reader will know of many authors
whether they generally provide valuable information or not. If not, reject the
article. If the authors are unknown, give them the benefit of the doubt.
3. Read the abstract. The main point here is to decide whether the conclusion is
important to you. If not, reject the article.
4. Consider the site to see if it is sufficiently similar to your own situation, and
decide whether the conclusion may be applicable to your work. For example, a
conclusion from research in a hospital may not be relevant for primary care. If
the site differs too much from your own situation, reject the article.
5. Check the materials and methods section. Only by knowing and accepting
the research method can you decide whether the conclusion is valid.
6. Check the references. If you know the subject you will probably be able to
judge whether the authors have included the key references in that field. If these
are missing, be careful.
Clinical trials
86
Chapter 12
It is beyond the scope of this book to go into the details of how reports on clinical
trials should be assessed, but a few general principles are given here. Generally,
only randomized, double-blind clinical trials give valid information about the
effectiveness of a treatment. Conclusions drawn from studies of other design may
be biased.
Second, a complete description of a clinical trial should include (1) the patients in
the trial, with number, age, sex, criteria for inclusion and exclusion; (2)
administration of the drug(s): dose, route, frequency, checks on non-adherence to
treatment, duration; (3) methods of data collection and assessment of therapeutic
effects; and (4) a description of statistical tests and measures to control for bias.
Finally you should look at the clinical relevance of the conclusion, not only its
statistical significance. Many statistical differences are too small to be clinically
relevant.
Sometimes conflicting evidence is presented by different sources. If in doubt, first
check on the methodology, because different methods may give different results.
Then look at the population studied to see which one is more relevant to your
situation. If doubts remain, it is better to wait and to postpone a decision on your Pdrug choice until more evidence has emerged.
Conclusion
Keeping up-to-date should not be too difficult for prescribers in developed
countries; it can be far from easy in some parts of the world where access to
independent sources of drug information is very limited. But wherever you live and
work it is important to develop a strategy to maximize your access to the key
information you need for optimal benefit of the drugs you prescribe. Be aware of
the limitations of some types of information, and spend your time on information
that is worth it.
87
88
Annex 1
A
nnexes
Annex 1:
page
Annex 2:
Essential references..................................................................................85
Annex 3:
How to explain the use of some dosage forms..........................................87
Annex 4:
The use of injections...............................................................................101
89
90
Annex 1
91
nnex 1
Introduction
Pharmacology describes the interaction between drugs and organisms. In this
interaction two features are especially important. Pharmacodynamics deals with
the effects of a drug on the body; how a drug acts and its side effects, in which
tissues, at which receptor sites, at which concentration, etc. The effects of drugs
may be altered by other drugs or disease states. Antagonism, synergism, addition
and other phenomena are also described by pharmacodynamics.
Pharmacokinetics deals with the effects of the body on the drug, through
Absorption, Distribution, Metabolism and Excretion (ADME).
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Annex 1
The dynamics and kinetics of a drug determine its therapeutic usefulness. The
pharmacodynamics of a drug determine its effectiveness and which side effects
may occur, and at what concentration. The prescriber has very little influence on
this. The pharmacokinetics of a drug determine how often, in what quantity and
dosage form and for how long the drug should be given to reach and maintain the
required plasma concentration. As the prescriber can actively influence the
process, the following section concentrates on this aspect.
Pharmacodynamics
The effects of a drug are usually presented in a dose-response curve. The effect
of the drug is plotted on the Y-axis and the dose on the X-axis (Figure 10). The
dose is usually plotted on a logarithmic scale. The higher the dose the stronger the
effect, until the effect levels off to a maximum. The effect is usually expressed as a
percentage of the maximum. The maximum effect of one drug may be more than
that of another. Desired and side effects can both be plotted in dose-response
curves.
2
The dose is usually expressed per kilogram body weight or per m body surface
area. However, the most accurate way is to use the plasma concentration, because
it excludes differences in absorption and elimination of the drug. In the following
text the plasma concentration-response curve (Cp/response curve) is used.
The Cp/response curve
The shape of the Cp/response curve is determined by pharmacodynamic factors.
Cp/response curves reflect the result in a number of individuals, referred to as a
population. If the plasma concentration is lower than where the curve begins, 0%
of the population will experience an effect. An effect of 50% means that the
average effect in the total population is 50% of the maximum (and not a 50% effect
in one individual) (Figure 10).
Unfortunately, most drugs have a Cp/response curve for side effects as well. This
curve should be interpreted in the same way as Cp/response curves. The two
curves together define the minimum and maximum plasma concentrations. The
concentration that gives the minimum useful effect is the therapeutic threshold,
93
while the plasma concentration at which the maximum tolerated side effects occur
is called the therapeutic ceiling. Remember that Cp/response curves represent
the dynamics in a group of patients, and can only offer a guideline when thinking in
terms of an individual patient.
Pharmacokinetics
A dose is usually repeated over a certain period. The plasma concentration in one
or more patients during a certain period is depicted in a so called plasma
concentration/time curve (Cp/time curve). Figure 11 shows the Cp/time curve of
the first 7 days after starting treatment.
94
Annex 1
95
The position and the width of the window are determined by pharmacodynamic
factors (Figure 14). The position of the window may shift upwards in case of
resistance by the patient or competitive antagonism by another drug: a higher
plasma concentration is needed to exert the same effect. The window can shift
downwards in case of hypersensitization or synergism by another drug: a lower
plasma concentration is needed.
The width of the window may also vary. It may become narrower in case of a
decreased safety-margin. For example, the therapeutic window of theophylline is
narrower in small children than in adults. A broader window usually has no
consequences.
Curve
The profile of the curve is determined by four factors: Absorption, Distribution,
Metabolism and Excretion. These are usually referred to as ADME factors.
Although most treatments consist of more than one dose of a drug, some
pharmacokinetic parameters can best be
explained by looking at the effect of one dose
only.
One of the most important parameters is the half-life of a drug (Figure 15). Most
drugs are eliminated by means of a first-order process. This means that per unit
of time the same percentage of drug is eliminated, for example 6% per hour. The
half-life of a drug is the time it takes to decrease the plasma concentration to half of
its initial value. With 6% per hour the half-life is about 11 hours (if no more of the
drug is given in the meantime). After 2 half-lives (22 hours) it will be 25%; after 3
half-lives 12.5%; and after 4 half-lives 6.25%. If the original plasma concentration
falls within the therapeutic window, a decline to 6.25% will usually be far below the
therapeutic threshold. For this reason it is usually said that drugs no longer have a
pharmacological effect 4 half-lives after the last dose.
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Annex 1
Drug treatment
The total Cp/time curve is influenced by three actions by the prescriber: starting the
drug-treatment; steady state treatment; stopping the treatment. All have a distinct
effect on the curve.
Starting drug treatment
The most important issue in starting treatment is
the speed at which the curve reaches steady state,
within the therapeutic window. If you give a fixed
dose per unit of time, this speed is only determined
by the half-life of the drug. On a fixed dosage
schedule, steady state is reached after about 4
half-lives (Figure 16). In case of a long half-life it
may therefore take some time for the drug to reach
a therapeutic concentration. If you want to reach
the window quicker, you can use a loading dose
(see below).
If you decide to raise the dose it will again take about 4 half-lives before you reach
the new steady state. The same applies when you decrease it by giving a lower
dose.
Stopping drug treatment
For drugs with first-order elimination kinetics the plasma concentration decreases
by 50% each half-life period, if no more of the drug is taken (Figure 18). The effect
of the drug stops when the concentration falls below the therapeutic threshold. For
example, if the initial plasma concentration is 300 ug/ml, the therapeutic threshold
75 ug/ml and the half-life 8 hours, this will take 16 hours (2 half-lives). This principle
applies equally to drugs taken in overdose.
Some drugs are eliminated by zero-order elimination process. This means that
the same amount of drug is eliminated per period of time. For example, 100 mg is
eliminated per day, regardless of whether the total amount in the body is 600 mg or
20 grams. Such drugs do not have a half-life. This also means that the Cp/time
curve never levels off to a certain maximum: the plasma concentration can rise
forever if more of the drug is administered than the body can eliminate. To maintain
a steady state you will have to administer exactly the amount that the body
eliminates. The dosage of drugs in this category requires great care because of the
increased risk of accumulation. Fortunately only a few such drugs exist. Examples
are phenytoin, dicoumarol and probenicid. Acetylsalicylic acid in high dosage
(grams per day) also behaves like this. And so does alcohol!
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99
A
nnex 2
Essential references
Practical low-cost books on drugs and prescribing
National essential drugs list, national formulary, hospital formulary,
institutional and national treatment guidelines. These are essential tools in your
prescribing, as they indicate which drugs are recommended and available in the
health system. If these references do not exist:
WHO Model List of Essential Drugs. See: The use of essential drugs
(containing the latest model list) under WHO publications on p.86. In the absence
of a national list, the WHO model list offers a good indication of effective, safe and
relatively cheap essential drugs within each therapeutic category.
WHO treatment guidelines for common diseases, such as acute respiratory
tract infections, diarrhoeal diseases, malaria and other parasitic diseases, sexually
transmitted diseases, tuberculosis, leprosy and others. These are very useful
references, based on international expert consensus. In many cases they are used
by countries when developing their national treatment guidelines.
British National Formulary. London: British Medical Association & The
Pharmaceutical Society of Great Britain. This is a highly respected reference work
containing essential information on a selection of drugs available on the UK
market, with price indication. There are short evaluative statements for each
therapeutic group. Although revised every six months, old issues remain a valuable
source of information and may be available to you at no or very low cost.
Clinical Guidelines - Diagnostic and Treatment Manual. Paris: Mdecins sans
Frontires. Editions Hatier, 1990. This is a very practical book, which is largely
based on WHO treatment guidelines for common diseases.
100
Annex 2
USP DI, Vol. 1.: Drug Information for the Health Care Provider, Vol. 2.:
Information for the Patient. Under authority of the United States Pharmacopeial
Convention Inc., 12601 Twinbrook Parkway, Rockville, Maryland 20832, USA.
Drug bulletins
Drug and Therapeutics Bulletin, Consumers Association, 14 Buckingham Street,
London WC2N 6DS, UK. Published fortnightly; offers comparative assessments of
therapeutic value of different drugs and treatments.
Prescrire International, Association Mieux Prescrire, BP 459, 75527 Paris Cedex
ll, France. Published quarterly; provides English translations of selected articles on
clinical pharmacology, ethical and legal aspects of drugs, which have appeared in
La Revue Prescrire.
The Medical Letter, The Medical Letter Inc. 56 Harrison Street, New Rochelle, NY
10801, USA. Published fortnightly; provides comparative drug profiles and advice
on the choice of drugs for specific problems.
If you want to check whether an independent drug bulletin is published in your
country contact: The International Society of Drug Bulletins, l03 Hertford Road,
London N2 9BX, UK, or the WHO Action Programme on Essential Drugs.
WHO publications
The Use of Essential Drugs (including the 8th Model List of Essential Drugs).
Geneva: World Health Organization, 1995. Technical Report Series 850. This
booklet also contains the criteria for the selection of essential drugs and information
on applications of the model list. The book is updated every two years.
WHO Model Prescribing Information. Geneva: World Health Organization. A
series of authoritative booklets with unbiased drug information for the prescriber,
including most drugs on the WHO Model List of Essential Drugs. Each module
deals with one therapeutic group. The series is not yet complete.
WHO Ethical Criteria for Medicinal Drug Promotion. Geneva: World Health
Organization, 1988. This is the text of a WHO statement adopted by the World
Health Assembly of 1988, setting out general principles which could be adapted by
governments to national circumstances. Reprinted in Essential Drugs Monitor 17.
WHO Drug Information. Geneva: World Health Organization. A quarterly journal
that provides an overview of topics relating to drug development and regulation. It
seeks to relate regulatory activity to therapeutic practice.
International Nonproprietary Names (INN) for Pharmaceutical Substances.
Geneva: World Health Organization, 1992. This book contains an updated
cumulative list of officially approved generic names in Latin, English, French,
Russian and Spanish.
Essential Drugs Monitor, Geneva: World Health Organization, Action Programme
on Essential Drugs. Free of charge and published three times per year; contains
regular features on issues related to the rational use of drugs, including drug policy,
research, education and training, and a review of new publications.
101
nnex 3
Table of contents
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
102
page
Eye drops.........................................................................................................88
Eye ointment....................................................................................................89
Ear drops......................................................................................................... 90
Nasal drops......................................................................................................91
Nasal spray......................................................................................................92
Transdermal patch...........................................................................................93
Aerosol............................................................................................................. 94
Inhaler with capsules.......................................................................................95
Suppositories...................................................................................................96
Vaginal tablet with applicator............................................................................97
Vaginal tablet without applicator.......................................................................98
Vaginal cream, ointment and gel......................................................................99
Annex 3
CHECKLIST 1
Eye drops
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Steps 4 and 5
CHECKLIST 2
Eye ointment
1.
2.
3.
4.
5.
6.
7.
8.
9.
Steps 4 and 5
104
Annex 3
CHECKLIST 3
Ear drops
1.
2.
3.
4.
5.
6.
7.
Warm the ear-drops by keeping them in the hand or the armpit for several
minutes. Do not use hot water tap, no temperature control!
Tilt head sideways or lie on one side with the ear upward.
Gently pull the lobe to expose the ear canal.
Apply the amount of drops prescribed.
Wait five minutes before turning to the other ear.
Use cotton wool to close the ear canal after applying the drops ONLY if the
manufacturer explicitly recommends this.
Ear-drops should not burn or sting longer than a few minutes.
Step 1
Steps 2 and 3
Step 6
105
CHECKLIST 4
Nasal drops
1.
2.
3.
4.
5.
6.
7.
8.
Steps 2 and 3
106
Step 5
Annex 3
CHECKLIST 5
Nasal spray
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Steps 4 and 5
Step 7
107
CHECKLIST 6
Transdermal patch
1.
2.
3.
4.
6.
7.
8.
9.
For patch site see instructions included with the drug or check with your
pharmacist.
Do not apply over bruised or damaged skin.
Do not wear over skin folds or under tight clothing and change spots regularly.
Apply with clean, dry hands.
Clean and dry the area of application completely.
Remove patch from package, do not touch drug side.
Place on skin and press firmly. Rub the edges to seal.
Remove and replace according to instructions.
Step 7
108
Step 8
Annex 3
CHECKLIST 7
Aerosol
1.
2.
3.
4.
5.
6.
8.
9.
10.
11.
Steps 4 and 5
Step 8
109
CHECKLIST 8
Inhaler with capsules
1.
2.
3.
4.
5.
6.
7.
8.
9.
Step 4
110
Step 5
Annex 3
CHECKLIST 9
Suppository
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Step 6
111
CHECKLIST 10
Vaginal tablet with applicator
1.
2
3.
4.
5.
6.
7.
8.
9.
10.
Steps 4 and 5
112
Step 6
Annex 3
CHECKLIST 11
Vaginal tablet without applicator
1.
2.
3.
4.
5.
6.
Steps 4 and 5
113
CHECKLIST 12
Applying vaginal creams, ointments and gels
(most of these drugs come with an applicator)
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Steps 4 and 5
114
Steps 7 and 8
Annex 3
115
nnex 4
Table of contents
page
Annex 4
4.
5.
6.
Subcutaneous injection..................................................................................106
Intramuscular injection...................................................................................107
Intravenous injection......................................................................................108
117
Expiry dates
Check the expiry dates of each item including the drug.
If you make housecalls, check the drugs in your medical bag regularly to
make sure that they have not passed the expiry date.
2.
Drug
Make sure that the vial or ampoule contains the right drug in the right
strength.
3.
Sterility
During the whole preparation procedure, material should be kept sterile.
Wash your hands before starting to prepare the injection.
Disinfect the skin over the injection site.
4.
No bubbles
Make sure that there are no air bubbles left in the syringe.
This is more important in intravenous injections.
5.
Prudence
Once the protective cover of the needle is removed extra care is needed.
Do not touch anything with the unprotected needle.
Once the injection has been given take care not to prick yourself or somebody
else.
6.
Waste
Make sure that contaminated waste is disposed of safely.
118
Annex 4
CHECKLIST 1
Aspirating from ampoules
(glass, plastic)
Materials needed
Syringe of appropriate size, needle of required size, ampoule with required drug or
solution, gauze.
Technique
1. Wash your hands.
2. Put the needle on the syringe.
3. Remove the liquid from the neck of the ampoule by flicking it or swinging it
fast in a downward spiralling movement.
4. File around the neck of the ampoule.
5. Protect your fingers with gauze if ampoule is made of glass.
6. Carefully break off the top of the ampoule (for a plastic ampoule twist the top).
7. Aspirate the fluid from the ampoule.
8. Remove any air from the syringe.
9. Clean up; dispose of working needle safely; wash your hands.
Step 4
Step 5
Step 6
119
CHECKLIST 2
Aspirating from a vial
Materials needed
Vial with required drug or solution, syringe of the appropriate size, needle of right
size (im, sc, or iv) on syringe, disinfectant, gauze.
Technique
1. Wash your hands.
2. Disinfect the top of the vial.
3. Use a syringe with a volume of twice the required amount of drug or solution
and add the needle.
4. Suck up as much air as the amount of solution needed to aspirate.
5. Insert needle into (top of) vial and turn upside-down.
6. Pump air into vial (creating pressure).
7. Aspirate the required amount of solution and 0.1 ml extra. Make sure the tip of
the needle is below the fluid surface.
8. Pull the needle out of the vial.
9. Remove possible air from the syringe.
10. Clean up; dispose of waste safely; wash your hands.
Step 4
120
Step 6
Step 7
Annex 4
CHECKLIST 3
Dissolving dry medicine
Materials needed
Vial with dry medicine to be dissolved, syringe with the right amount of solvent,
needle of right size (iv, sc or iv) on syringe, disinfectant, injection needle, gauze.
Technique
1. Wash hands.
2. Disinfect the rubber cap (top) of the vial containing the dry medicine.
3. Insert the needle into the vial, hold the whole upright.
4. Suck up as much air as the amount of solvent already in the syringe.
5. Inject only the fluid into the vial, not the air!
6. Shake.
7. Turn the vial upside-down.
8. Inject the air into the vial (creating pressure).
9. Aspirate the total amount of solution (no air).
10. Remove any air from the syringe.
11. Clean up; dispose of waste safely; wash hands.
Step 4
Step 5
Step 8
121
CHECKLIST 4
Subcutaneous injection
Materials needed
Syringe with the drug to be administered (without air), needle (Gauss 25, short and
thin; on syringe), liquid disinfectant, cotton wool, adhesive tape.
Technique
1. Wash hands.
2. Reassure the patient and explain the procedure.
3. Uncover the area to be injected (upper arm, upper leg, abdomen).
4. Disinfect skin.
5. Pinch fold of the skin.
6. Insert needle in the base of the skin-fold at an angle of 20 to 30 degrees.
7. Release skin.
8. Aspirate briefly; if blood appears: withdraw needle, replace it with a new one,
if possible, and start again from point 4.
9. Inject slowly (0.5 - 2 minutes!).
10. Withdraw needle quickly.
11. Press sterile cotton wool onto the opening. Fix with adhesive tape.
12. Check the patient's reaction and give additional reassurance, if necessary.
13. Clean up; dispose of waste safely; wash hands.
Step 3
122
Step 5
Step 6
Annex 4
CHECKLIST 5
Intramuscular injection
Materials needed
Syringe with the drug to be administered (without air), needle (Gauss 22, long and
medium thickness; on syringe), liquid disinfectant, cotton wool, adhesive tape.
Technique
1. Wash hands.
2. Reassure the patient and explain the procedure.
3. Uncover the area to be injected (lateral upper quadrant major gluteal muscle,
lateral side of upper leg, deltoid muscle).
4. Disinfect the skin.
5. Tell the patient to relax the muscle.
6. Insert the needle swiftly at an angle of 90 degrees (watch depth!).
7. Aspirate briefly; if blood appears, withdraw needle. Replace it with a new one,
if possible, and start again from point 4.
8. Inject slowly (less painful).
9. Withdraw needle swiftly.
10. Press sterile cotton wool onto the opening. Fix with adhesive tape.
11. Check the patient's reaction and give additional reassurance, if necessary.
12. Clean up; dispose of waste safely; wash your hands.
Step 4
Step 5
Step 6
123
CHECKLIST 6
Intravenous injection
Materials needed
Syringe with the drug to be administered (without air), needle (Gauss 20, long and
medium thickness; on syringe), liquid disinfectant, cotton wool, adhesive tape,
tourniquet.
Technique
1. Wash your hands.
2. Reassure the patient and explain the procedure.
3. Uncover arm completely.
4. Have the patient relax and support his arm below the vein to be used.
5. Apply tourniquet and look for a suitable vein.
6. Wait for the vein to swell.
7. Disinfect skin.
8. Stabilize the vein by pulling the skin taut in the longitudinal direction of the
vein. Do this with the hand you are not going to use for inserting the needle.
9. Insert the needle at an angle of around 35 degrees.
10. Puncture the skin and move the needle slightly into the vein (3-5 mm).
11. Hold the syringe and needle steady.
12. Aspirate. If blood appears hold the syringe steady, you are in the vein. If it
does not come, try again.
13. Loosen tourniquet.
14. Inject (very) slowly. Check for pain, swelling, hematoma; if in doubt whether
you are still in the vein aspirate again!
15. Withdraw needle swiftly. Press sterile cotton wool onto the opening. Secure
with adhesive tape.
16. Check the patient's reactions and give additional reassurance, if necessary.
17. Clean up; dispose of waste safely; wash your hands.
Step 8
124
Step 9
Steps 11 to 14
Annex 4
125
126